The present application represents U.S. national stage of internationl application PCT/SE96/01011, with an international filing date of Aug. 14 1996. The international application was published in English under Article 22(2) of the PCT. It claims priority to Swedish application 9502877-5 filed on Aug. 18, 1995, and to Swedish application 9503924-4 filed on Nov. 7, 1995.
The present invention relates to opioid-like peptide compounds. More particularly, it relates to opioid-like peptide compounds that exhibit peripheral analgesic activity and selectivity for the xcexc subtype of opioid receptors.
Many endogenous peptides of mammalian and amphibian origin bind to specific opioid receptors and elicit an analgesic response similar to classic narcotic opiates. Many different types of opioid receptors have been shown to coexist in higher animals. For example, see W. Martin et al., J. Pharmacol. Exp. Ther., 197, p. 517(1975); and J. Lord et al., Nature(London) ,257 p. 495(1977). Three different types of opioid receptors have been identified. The first, xcex4, shows a differentiating affinity for enkephalin-like peptides. The second, xcexc, shows enhanced selectivity for morphine and other poly-cyclic alkaloids. The third, xcexa, exhibits equal affinity for either group of the above ligands and preferential affinity for dynorphin. In general, the xcexc-receptors seem to be more involved with analgesic effects. The xcex4-receptors appear to deal with behavioral effects, although the xcex4 and the xcexa-receptors may also mediate analgesia.
Each opioid receptor, when coupled with an opiate, causes a specific biological response unique to that type of receptor. When an opiate activates more than one receptor, the biological response for each receptor is affected, thereby producing side effects. The less specific and selective an opiate may be, the greater the chance of causing increased side effects by the administration of the opiate.
In the prior art, opiates, opioid peptides, and analogs thereof, have either failed to demonstrate, or have demonstrated a limited degree of selectivity for the type of receptor, or receptors, to which they bind.
Opiates can cause serious and potentially fatal side effects. Side effects such as respiratory depression, tolerance, physical dependence capacity, and precipitated withdrawal syndrome are caused by nonspecific interactions with central nervous system receptors. See K. Budd, In International Encyclopedia of Pharmacology and Therapeutics; N. E. Williams and H. Wilkinson, Eds., Pergammon: (Oxford), 112, p.51 (1983). Therefore, opioid analgesics acting principally through opioid receptors in the peripheral nervous system would not be expected to cause similar unwanted side effects as those side effects associated with opioid analgesics affecting the central nervous system.
To date, one of the few classes of agents known to exert peripheral analgesic effects are non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, and ketorolac. These agents do not interact with opioid receptors but are known to inhibit cyclooxygenase and attenuate prostaglandin synthesis. These weak analgesics do not have centrally mediated side effects, but they can cause other side effects such as ulcerations of the gastro-intestinal tract.
It was thought that non-polar peptides pass more easily into the central nervous system than polar peptides by traversing the blood-brain barrier. It has been published that TAPP(H-Tyr-D-Ala-Phe-Phe-NH2) exhibited antinociceptive properties both peripherally and centrally (P. Schiller et al., Proceedings of the 20th European Peptide Symposium, 1988). In contradiction, it has been found by the present inventor that this tetrapeptide does not act centrally even at doses of 100 mg/kg.
It is an object of the invention to provide opioid-like peptide compounds which act peripherally but substantially avoid the unwanted side effects associated with conventional peripherally acting analgesics. It is a further object to provide peptide compounds which bind selectively to the xcexc-opioid receptor.
The present invention provides novel peptide compounds which act peripherally and are selective for xcexc-opioid receptors, the compound represented by formula (1): 
and salts, derivatives and analogues thereof
wherein,
R1 is Tyr or 2xe2x80x2,6xe2x80x2-dimethyltyrosine, or an analog or derivative thereof;
R2 is D-Ala or D-Arg;
R3 is Phe(p-F);
R4 is Phe or Phe(p-F);
X is H or C1-6alkyl; and
Y and Z are independently H, aralkyl or C1-6alkyl.
In another aspect of the invention, there is provided pharmaceutical compositions comprising a compound of formula (1) in admixture with a pharmaceutically acceptable carrier and/or a second therapeutically active agent.
In a further aspect of the invention, there is provided a method of treating pain comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of formula (1).
In a further aspect of the invention, there is provided the use of a compound of formula (1)for the manufacture of a medicament for treating pain.